Treatment of cataplexy

ABSTRACT

The present invention relates to a method of treating cataplexy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of certain carbamate compounds.

STATEMENT OF PRIORITY

The present invention claims the benefit, under 35 U.S.C. §119(e), ofU.S. Provisional Application No. 61/778,998, filed Mar. 13, 2013, theentire contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to a method of treating cataplexy in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of certain carbamate compounds.

BACKGROUND

Cataplexy is a sudden and transient episode of loss of muscle tone,often triggered by emotions such as laughter, fear, anger, frustration,annoyance, nervousness, embarrassment, and sadness. The sudden loss ofmuscle tone in cataplexy is similar to rapid eye movement(REM)-associated muscle atonia during sleep, but it is occurring duringwakefulness. A cataplectic attack is sudden in onset and is localized toa specific muscle group or parts of the body. The subject is lucidduring this attack; consciousness is always maintained at the onset ofcataplexy. A full-blown attack may occur and results in complete muscleparalysis with postural collapse and possible injury. However, mostoften patients with postural collapse have the capability to avoidinjury because the fall is slow and progressive. The more commonlylimited cataplectic attacks involve the head and face, neck, upper limb,and more rarely lower limb known as “knee buckling.” Attacks can lastfrom a few seconds up to ten minutes, and may occur up to several timesper week. In some patients, status cataplecticus, or periods ofrepetitive loss of muscle tone, occurs and can last for hours or days.

Cataplexy is a rare disease (prevalence of fewer than 5 per 10,000 inthe community), but affects roughly 70% of people who have narcolepsy.However, in some cases, cataplexy occurs without the co-occurrence ofnarcolepsy. Furthermore, upwards of 30% of patients with narcolepsy maynever experience cataplexy. The exact cause of cataplexy is unknown, butthe condition is strongly linked to experiencing intense emotions andreduced levels of the neurotransmitter hypocretin. Cataplexy isconsidered secondary when it is due to specific lesions in the brainthat cause a depletion of the hypocretin neurotransmitter. Cataplexy canalso be present as a side effect of discontinuation of certain drugs,such as selective serotonin re-uptake inhibitor (SSRI) antidepressants.

Cataplexy, whether associated with narcolepsy or other causes, isdisabling and potentially dangerous. Regardless of cause, cataplexy islinked to a variety of transportation and industrial accidents and causedecreased job performance and considerable subjective distress. Atherapeutic agent that reduces or eliminates cataplexy would haveimportant implications not only for individual patients, but also forpublic health and safety.

SUMMARY OF EMBODIMENTS OF THE INVENTION

The present invention is directed to a method of treating cataplexy in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt or ester thereof, wherein R is amember selected from the group consisting of alkyl of 1 to 8 carbonatoms, halogen, alkoxy containing 1 to 3 carbon atoms, nitro, hydroxy,trifluoromethyl, and thioalkoxy containing 1 to 3 carbon atoms; x is aninteger of 0 to 3, with the proviso that R may be the same or differentwhen x is 2 or 3; R₁ and R₂ can be the same or different from each otherand are independently selected from the group consisting of hydrogen,lower alkyl of 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl of 3 to7 carbon atoms; or R₁ and R₂ can be joined to form a 5 to 7-memberedheterocycle optionally substituted with a member selected from the groupconsisting of alkyl and aryl groups, wherein the heterocycle cancomprise 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein thenitrogen atoms are not directly connected with each other or with theoxygen atom.

Embodiments of the invention include a method of treating cataplexy in asubject in need thereof, comprising the step of administering to thesubject a therapeutically effective amount of an enantiomer of Formula Isubstantially free of other enantiomers or an enantiomeric mixturewherein one enantiomer of Formula I predominates.

In some embodiments, the compound of Formula I is a compound of FormulaIa:

or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, the compound of Formula I is a compound of FormulaIb:

or a pharmaceutically acceptable salt or ester thereof. This compound isnamed (R)-(beta-amino-benzenepropyl) carbamate orO-carbamoyl-(D)-phenylalaninol and has alternatively been calledADX-N05, SKL-N05, YKP10A, and R228060.

Embodiments of the invention include the use, for the preparation of amedicament for the treatment of cataplexy, of an enantiomer of Formula Isubstantially free of other enantiomers or an enantiomeric mixturewherein one enantiomer of Formula I predominates.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The present invention now will be described hereinafter with referenceto the accompanying drawings and examples, in which embodiments of theinvention are shown. This invention may, however, be embodied in manydifferent forms and should not be construed as limited to theembodiments set forth herein. Rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. The terminology used in thedescription of the invention herein is for the purpose of describingparticular embodiments only and is not intended to be limiting of theinvention.

Unless the context indicates otherwise, it is specifically intended thatthe various features of the invention described herein can be used inany combination. Moreover, the present invention also contemplates thatin some embodiments of the invention, any feature or combination offeatures set forth herein can be excluded or omitted. To illustrate, ifthe specification states that a composition comprises components A, Band C, it is specifically intended that any of A, B or C, or acombination thereof, can be omitted and disclaimed singularly or in anycombination.

DEFINITIONS

As used herein, “a,” “an,” or “the” can mean one or more than one. Forexample, “a” cell can mean a single cell or a multiplicity of cells.

Also as used herein, “and/or” refers to and encompasses any and allpossible combinations of one or more of the associated listed items, aswell as the lack of combinations when interpreted in the alternative(“or”).

The term “about,” as used herein when referring to a measurable valuesuch as an amount of dose (e.g., an amount of a compound) and the like,is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or even±0.1% of the specified amount.

The terms “comprise,” “comprises,” and “comprising” as used herein,specify the presence of the stated features, integers, steps,operations, elements, and/or components, but do not preclude thepresence or addition of one or more other features, integers, steps,operations, elements, components, and/or groups thereof.

As used herein, the transitional phrase “consisting essentially of”means that the scope of a claim is to be interpreted to encompass thespecified materials or steps recited in the claim “and those that do notmaterially affect the basic and novel characteristic(s)” of the claimedinvention. See, In re Herz, 537 F.2d 549, 551-52, 190 U.S.P.Q. 461, 463(CCPA 1976) (emphasis in the original); see also MPEP §2111.03. Thus,the term “consisting essentially of” when used in a claim or thedescription of this invention is not intended to be interpreted to beequivalent to “comprising.”

As used herein, the terms “increase,” “increases,” “increased,”“increasing,” and similar terms indicate an elevation of at least about25%, 50%, 75%, 100%, 150%, 200%, 300%, 400%, 500% or more.

As used herein, the terms “reduce,” “reduces,” “reduced,” “reduction,”and similar terms mean a decrease of at least about 5%, 10%, 15%, 20%,25%, 35%, 50%, 75%. 80%, 85%, 90%, 95%, 97% or more. In particularembodiments, the reduction results in no or essentially no (i.e., aninsignificant amount, e.g., less than about 10% or even 5%) detectableactivity or amount.

“Effective amount” as used herein refers to an amount of a compound,composition and/or formulation of the invention that is sufficient toproduce a desired effect, which can be a therapeutic and/or beneficialeffect. The effective amount will vary with the age, general conditionof the subject, the severity of the condition being treated, theparticular agent administered, the duration of the treatment, the natureof any concurrent treatment, the pharmaceutically acceptable carrierused, and like factors within the knowledge and expertise of thoseskilled in the art. As appropriate, an “effective amount” in anyindividual case can be determined by one of skill in the art byreference to the pertinent texts and literature and/or by using routineexperimentation.

By the term “treat,” “treating,” or “treatment of” (and grammaticalvariations thereof) it is meant that the severity of the subject'scondition is reduced, at least partially improved or ameliorated and/orthat some alleviation, mitigation or decrease in at least one clinicalsymptom is achieved and/or there is a delay in the progression of thedisease or disorder. With respect to cataplexy, the term refers to adecrease in the number of attacks, a decrease in the length of attacks,and/or a decrease in the severity of attacks. For example, treatment mayproduce a decrease in the number of cataplectic events per week of atleast about 20%, e.g., at least about 30%, 40%, 50%, 60%, 70%, 80%, ormore.

A “treatment effective” amount as used herein is an amount that issufficient to treat (as defined herein) the subject. Those skilled theart will appreciate that the therapeutic effects need not be complete orcurative, as long as some benefit is provided to the subject.

A “subject” of the invention includes any animal that has or issuspected of having cataplexy. Such a subject is generally a mammaliansubject (e.g., a laboratory animal such as a rat, mouse, guinea pig,rabbit, primate, etc.), a farm or commercial animal (e.g., a cow, horse,goat, donkey, sheep, etc.), or a domestic animal (e.g., cat, dog,ferret, etc.). In particular embodiments, the subject is a primatesubject, a non-human primate subject (e.g., a chimpanzee, baboon,monkey, gorilla, etc.) or a human. In certain embodiments, a subject ofthe invention can be a subject known to have or believed to havecataplexy. A subject of the invention can be a subject known or believedto be at risk of developing cataplexy. Alternatively, a subjectaccording to the invention can also include a subject not previouslyknown or suspected to have cataplexy. In embodiments of the inventionthe subject has or is suspected of having narcolepsy. Subjects includemales and/or females of any age, including neonates, juvenile, matureand geriatric subjects.

A “subject in need” of the methods of the invention can be a subjectknown to have cataplexy, suspected of having cataplexy, or having anincreased risk of developing cataplexy. In some embodiments, a “subjectin need” is one that has moderate or severe cataplexy, e.g., a subjecthaving 3 or more cataplectic events a week, e.g., 4, 5, 6, 7, 8, 9, or10 or more cataplectic events a week.

The term “pharmaceutically acceptable salts or esters” shall meannon-toxic salts or esters of the compounds employed in this inventionwhich are generally prepared by reacting the free acid with a suitableorganic or inorganic base or the free base with a suitable organic orinorganic acid. Examples of such salts include, but are not limited to,acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynapthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,oleate, oxalate, pamoate, palmitate, panthothenate,phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium,stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodide, and valerate.

As used herein the term “concomitant administration” or “combinationadministration” of a compound, therapeutic agent or known drug with acompound of the present invention means administration of a knownmedication or drug and, in addition, the one or more compounds of theinvention at such time that both the known drug and the compound willhave a therapeutic effect. In some cases this therapeutic effect will besynergistic. Such concomitant administration can involve concurrent(i.e., at the same time), prior, or subsequent administration of theknown drug with respect to the administration of a compound of thepresent invention. A person of skill in the art, would have nodifficulty determining the appropriate timing, sequence and dosages ofadministration for particular drugs and compounds of the presentinvention.

In addition, in some embodiments, the compounds of this invention willbe used, either alone or in combination with each other or incombination with one or more other therapeutic medications as describedabove, or their salts or esters, for manufacturing a medicament for thepurpose of providing treatment for cataplexy to a patient or subject inneed thereof.

The present invention is based in part on the discovery thatphenylalkylamino carbamates of Formula I have novel and uniquepharmacological properties. These compounds have been shown to have abeneficial effect on DREM and cataplexy. Although the precise mechanismof action is not completely understood, it is believed that thesecompounds do not work by the same mechanisms as most other knownstimulant drugs in producing their effects. For this reason thecompounds of Formula I are especially suitable for use as treatment forcataplexy. Thus, these compounds can be safely used for this purpose toprovide effective treatment of cataplexy regardless of the preciseetiology of the disorder.

One aspect of the invention relates to a method of treating cataplexy ina subject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt or ester thereof; wherein R is amember selected from the group consisting of lower alkyl of 1 to 8carbon atoms, halogen, alkoxy containing 1 to 3 carbon atoms, nitro,hydroxy, trifluoromethyl, and thioalkoxy containing 1 to 3 carbon atoms;x is an integer of 0 to 3, with the proviso that R may be the same ordifferent when x is 2 or 3; R₁ and R₂ are independently selected fromthe group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms,aryl, arylalkyl, cycloalkyl of 3 to 7 carbon atoms; or R₁ and R₂ can bejoined to form a 5 to 7-membered heterocycle optionally substituted witha member selected from the group consisting of alkyl, and aryl groups,wherein the heterocycle can comprise 1 to 2 nitrogen atoms and 0 to 1oxygen atom, wherein the nitrogen atoms are not directly connected witheach other or with the oxygen atom.

It is understood that substituents and substitution patterns on thecompounds of the present invention can be selected by one of skill inthe art to provide compounds that are chemically stable and that can bereadily synthesized by techniques known in the art as well as themethods provided herein.

In one embodiment, the compound of Formula I is a compound of FormulaIa:

or a pharmaceutically acceptable salt or ester thereof.

In one embodiment the compound of Formula I is the (D) enantiomerwherein R₁ and R₂ are hydrogen and x is 0 (compound Ib).

or a pharmaceutically acceptable salt or ester thereof. This compound isthe (R) enantiomer, if named by structure and is therefore(R)-(beta-amino-benzenepropyl) carbamate. This compound is thedextrorotary enantiomer and can therefore also be namedO-carbamoyl-(D)-phenylalaninol. The compound is also named ADX-NOS.These names may be used interchangeably in this specification.

The present invention includes the use of isolated enantiomers of thecompound of Formula I (e.g., compounds of Formula Ia or Ib). In oneembodiment, a pharmaceutical composition comprising the isolatedS-enantiomer of Formula I is used to provide treatment to a subject. Inanother embodiment, a pharmaceutical composition comprising the isolatedR-enantiomer of Formula I is used to provide treatment to a subject.

The present invention also includes the use of mixtures of enantiomersof Formula I. In one aspect of the present invention, one enantiomerwill predominate. An enantiomer that predominates in the mixture is onethat is present in the mixture in an amount greater than any of theother enantiomers present in the mixture, e.g., in an amount greaterthan 50%. In one aspect, one enantiomer will predominate to the extentof 90% or to the extent of 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98% orgreater. In one embodiment, the enantiomer that predominates in acomposition comprising a compound of Formula I is the S-enantiomer ofFormula I.

The present invention provides methods of using enantiomers andenantiomeric mixtures of compounds represented by Formula I. A carbamateenantiomer of Formula I contains an asymmetric chiral carbon at thebenzylic position, which is the second aliphatic carbon adjacent to thephenyl ring.

An enantiomer that is isolated is one that is substantially free of thecorresponding enantiomer. Thus, an isolated enantiomer refers to acompound that is separated via separation techniques or prepared free ofthe corresponding enantiomer.

The term “substantially free,” as used herein, means that the compoundis made up of a significantly greater proportion of one enantiomer. Inpreferred embodiments, the compound includes at least about 90% byweight of one enantiomer. In other embodiments of the invention, thecompound includes at least about 99% by weight of one enantiomer.

The compounds of Formula I can be synthesized by methods known to theskilled artisan. The salts and esters of the compounds of Formula I canbe produced by treating the compound with a suitable mineral or organicacid (HX) in suitable solvent or by other means well known to those ofskill in the art.

Details of reaction schemes for synthesizing compounds of Formula I aswell as representative examples on the preparation of specific compoundshave been described in U.S. Pat. No. 5,705,640, U.S. Pat. No. 5,756,817,U.S. Pat. No. 5,955,499, U.S. Pat. No. 6,140,532, all incorporatedherein by reference in their entirety.

From Formula I it is evident that some of the compounds of the inventionhave at least one and possibly more asymmetric carbon atoms. It isintended that the present invention include within its scope thestereochemically pure isomeric forms of the compounds as well as theirracemates. Stereochemically pure isomeric forms may be obtained by theapplication of art known principles. Diastereoisomers may be separatedby physical separation methods such as fractional crystallization andchromatographic techniques, and enantiomers may be separated from eachother by the selective crystallization of the diastereomeric salts withoptically active acids or bases or by chiral chromatography. Purestereoisomers may also be prepared synthetically from appropriatestereochemically pure starting materials, or by using stereoselectivereactions.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. Theprotecting groups may be removed at a convenient subsequent stage usingmethods known in the art.

The compound may be administered to a subject by any conventional routeof administration, including, but not limited to, oral, buccal, topical,systemic (e.g., transdermal, intranasal, or by suppository), orparenteral (e.g., intramuscular, subcutaneous, or intravenousinjection.) Administration of the compounds directly to the nervoussystem can include, for example, administration to intracerebral,intraventricular, intracerebralventricular, intrathecal, intracisternal,intraspinal or peri-spinal routes of administration by delivery viaintracranial or intravertebral needles or catheters with or without pumpdevices. Depending on the route of administration, compounds of FormulaI can be constituted into any form. For example, forms suitable for oraladministration include solid forms, such as pills, gelcaps, tablets,caplets, capsules, granules, and powders (each including immediaterelease, timed release and sustained release formulations). Formssuitable for oral administration also include liquid forms, such assolutions, syrups, elixirs, emulsions, and suspensions. In addition,forms useful for parenteral administration include sterile solutions,emulsions and suspensions.

In certain embodiments, pharmaceutical compositions of this inventioncomprise one or more compounds of Formula I or a salt or ester thereofwithout any pharmaceutical carriers or excipients. In other embodiments,pharmaceutical compositions of this invention comprise one or morecompounds of formula I or a salt or ester thereof intimately admixedwith a pharmaceutical carrier according to conventional pharmaceuticalcompounding techniques.

Carriers are inert pharmaceutical excipients, including, but not limitedto, binders, suspending agents, lubricants, flavorings, sweeteners,preservatives, dyes, and coatings. In preparing compositions in oraldosage form, any of the usual pharmaceutical carriers may be employed.For example, for liquid oral preparations, suitable carriers andadditives include water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like; for solid oralpreparations, suitable carriers and additives include starches, sugars,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like.

Compositions can take the form of tablets, pills, capsules, semisolids,powders, sustained release formulations, solutions, suspensions,emulsions, syrups, elixirs, aerosols, or any other appropriatecompositions; and comprise at least one compound of this invention,optionally in combination with at least one pharmaceutically acceptableexcipient. Suitable excipients are well known to persons of ordinaryskill in the art, and they, and the methods of formulating thecompositions, can be found in such standard references as Alfonso A R:Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton Pa., 1985, the disclosure of which is incorporated herein byreference in its entirety and for all purposes. Suitable liquidcarriers, especially for injectable solutions, include water, aqueoussaline solution, aqueous dextrose solution, and glycols.

The carbamate compounds can be provided as aqueous suspensions. Aqueoussuspensions of the invention can contain a carbamate compound inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients can include, for example, a suspendingagent, such as sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia, and dispersing or wetting agents such as anaturally occurring phosphatide (e.g., lecithin), a condensation productof an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),a condensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethylene oxycetanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensationproduct of ethylene oxide with a partial ester derived from fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).

The aqueous suspension can also contain one or more preservatives suchas ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Oil suspensions for use in the present methods can be formulated bysuspending a carbamate compound in a vegetable oil, such as arachis oil,olive oil, sesame oil or coconut oil, or in a mineral oil such as liquidparaffin, or a mixture of these. The oil suspensions can contain athickening agent, such as beeswax, hard paraffin or cetyl alcohol.Sweetening agents can be added to provide a palatable oral preparation,such as glycerol, sorbitol or sucrose. These formulations can bepreserved by the addition of an antioxidant such as ascorbic acid. As anexample of an injectable oil vehicle, see Minto, J. Pharmacol. Exp.Ther. 281:93 (1997). The pharmaceutical formulations of the inventioncan also be in the form of oil-in-water emulsions. The oily phase can bea vegetable oil or a mineral oil, as described above, or a mixture ofthese.

Suitable emulsifying agents include naturally occurring gums, such asgum acacia and gum tragacanth, naturally occurring phosphatides, such assoybean lecithin, esters or partial esters derived from fatty acids andhexitol anhydrides, such as sorbitan mono-oleate, and condensationproducts of these partial esters with ethylene oxide, such aspolyoxyethylene sorbitan mono-oleate. The emulsion can also containsweetening agents and flavoring agents, as in the formulation of syrupsand elixirs. Such formulations can also contain a demulcent, apreservative, or a coloring agent.

The compound of choice, alone or in combination with other suitablecomponents can be made into aerosol formulations (i.e., they can be“nebulized”) to be administered via inhalation. Aerosol formulations canbe placed into pressurized acceptable propellants, such asdichlorodifluoromethane, propane, nitrogen, and the like.

Formulations of the present invention suitable for parenteraladministration, such as, for example, by intraarticular (in the joints),intravenous, intramuscular, intradermal, intraperitoneal, andsubcutaneous routes, can include aqueous and non-aqueous, isotonicsterile injection solutions, which can contain antioxidants, buffers,bacteriostats, and solutes that render the formulation isotonic with theblood of the intended recipient, and aqueous and non-aqueous sterilesuspensions that can include suspending agents, solubilizers, thickeningagents, stabilizers, and preservatives. Among the acceptable vehiclesand solvents that can be employed are water and Ringer's solution, anisotonic sodium chloride. In addition, sterile fixed oils canconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid can likewisebe used in the preparation of injectables. These solutions are sterileand generally free of undesirable matter.

Where the compounds are sufficiently soluble they can be dissolveddirectly in normal saline with or without the use of suitable organicsolvents, such as propylene glycol or polyethylene glycol. Dispersionsof the finely divided compounds can be made-up in aqueous starch orsodium carboxymethyl cellulose solution, or in suitable oil, such asarachis oil. These formulations can be sterilized by conventional,well-known sterilization techniques. The formulations can containpharmaceutically acceptable auxiliary substances as required toapproximate physiological conditions such as pH adjusting and bufferingagents, toxicity adjusting agents, e.g., sodium acetate, sodiumchloride, potassium chloride, calcium chloride, sodium lactate and thelike.

The concentration of a carbamate compound in these formulations can varywidely, and will be selected primarily based on fluid volumes,viscosities, body weight, and the like, in accordance with theparticular mode of administration selected and the patient's needs. ForIV administration, the formulation can be a sterile injectablepreparation, such as a sterile injectable aqueous or oleaginoussuspension. This suspension can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,such as a solution of 1,3-butanediol. The formulations of commends canbe presented in unit-dose or multi-dose sealed containers, such asampoules and vials. Injection solutions and suspensions can be preparedfrom sterile powders, granules, and tablets of the kind previouslydescribed.

A carbamate compound suitable for use in the practice of this inventioncan be administered orally. The amount of a compound of the presentinvention in the composition can vary widely depending on the type ofcomposition, size of a unit dosage, kind of excipients, and otherfactors well known to those of skill in the art. In general, the finalcomposition can comprise, for example, from 0.000001 percent by weight(% w) to 100% w of the carbamate compound, e.g., 0.00001% w to 50% w,with the remainder being the excipient or excipients.

Pharmaceutical formulations for oral administration can be formulatedusing pharmaceutically acceptable carriers well known in the art indosages suitable for oral administration. Such carriers enable thepharmaceutical formulations to be formulated in unit dosage forms astablets, pills, powder, dragees, capsules, liquids, lozenges, gels,syrups, slurries, suspensions, etc. suitable for ingestion by thepatient. In other embodiments, pharmaceutical formulations for oraladministration can be formulated without using any pharmaceuticallyacceptable carriers.

Formulations suitable for oral administration can consist of (a) liquidsolutions, such as an effective amount of the pharmaceutical formulationsuspended in a diluents, such as water, saline or PEG 400; (b) capsules,sachets or tablets, each containing a predetermined amount of the activeingredient, as liquids, solids, granules or gelatin; (c) suspensions inan appropriate liquid; and (d) suitable emulsions.

Pharmaceutical preparations for oral use can be obtained throughcombination of the compounds of the present invention with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable additional compounds, ifdesired, to obtain tablets or dragee cores. Suitable solid excipientsare carbohydrate or protein fillers and include, but are not limited tosugars, including lactose, sucrose, mannitol, or sorbitol; starch fromcorn, wheat, rice, potato, or other plants; cellulose such as methylcellulose, hydroxymethyl cellulose, hydroxypropylmethyl-cellulose orsodium carboxymethylcellulose; and gums including arabic and tragacanth;as well as proteins such as gelatin and collagen.

If desired, disintegrating or solubilizing agents can be added, such ascross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate. Tablet forms can include one or moreof lactose, sucrose, mannitol, sorbitol, calcium phosphates, cornstarch, potato starch, microcrystalline cellulose, gelatin, colloidalsilicon dioxide, talc, magnesium stearate, stearic acid, and otherexcipients, colorants, fillers, binders, diluents, buffering agents,moistening agents, preservatives, flavoring agents, dyes, disintegratingagents, and pharmaceutically compatible carriers. Lozenge forms cancomprise the active ingredient in a flavor, e.g., sucrose, as well aspastilles comprising the active ingredient in an inert base, such asgelatin and glycerin or sucrose and acacia emulsions, gels, and the likecontaining, in addition to the active ingredient, carriers known in theart.

The compounds of the present invention can also be administered in theform of suppositories for rectal administration of the drug. Theseformulations can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperatures and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

The compounds of the present invention can also be administered byintranasal, intraocular, intravaginal, and intrarectal routes includingsuppositories, insufflation, powders and aerosol formulations (forexamples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187(1995); Tjwa, Ann. Allergy Asthma Immunol. 75:107 (1995)).

The compounds of the present invention can be delivered transdermally,by a topical route, formulated as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols.

Encapsulating materials can also be employed with the compounds of thepresent invention and the term “composition” can include the activeingredient in combination with an encapsulating material as aformulation, with or without other carriers. For example, the compoundsof the present invention can also be delivered as microspheres for slowrelease in the body. In one embodiment, microspheres can be administeredvia intradermal injection of drug (e.g., mifepristone)-containingmicrospheres, which slowly release subcutaneously (see Rao, J. Biomater.Sci. Polym. Ed. 7:623 (1995); as biodegradable and injectable gelformulations (see, e.g., Gao, Pharm. Res. 12:857 (1995)); or, asmicrospheres for oral administration (see, e.g., Eyles, J. Pharm.Pharmacol. 49:669 (1997)). Both transdermal and intradermal routesafford constant delivery for weeks or months. Cachets can also be usedin the delivery of the compounds of the present invention.

In another embodiment, the compounds of the present invention can bedelivered by the use of liposomes which fuse with the cellular membraneor are endocytosed, i.e., by employing ligands attached to the liposomethat bind to surface membrane protein receptors of the cell resulting inendocytosis. The active drug can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

By using liposomes, particularly where the liposome surface carriesligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thecarbamate compound into target cells in vivo (see, e.g., Al-Muhammed, J.Microencapsul. 13:293 (1996); Chonn, Curr. Opin. Biotechnol. 6:698(1995); Ostro, Am. J. Hosp. Pharm. 46:1576 (1989)).

Active drug may also be delivered by the use of monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Activedrug may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinyl-pyrrolidone, pyrancopolymer, polyhydroxy-propyl-methacrylamide-phenol,polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, active drug may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross linked or amphipathicblock copolymers of hydrogels.

In certain embodiments the compositions are in unit dosage forms such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, auto-injector devices or suppositories, for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation.

Alternatively, the composition may be presented in a form suitable foronce-weekly or once-monthly administration; for example, an insolublesalt of the active compound, such as the decanoate salt, may be adaptedto provide a depot preparation for intramuscular injection.

The pharmaceutical compositions herein will contain, per dosage unit,e.g., tablet, capsule, powder, injection, teaspoonful, suppository andthe like, an amount of the active ingredient necessary to deliver aneffective dose as described above. For example, the pharmaceuticalcompositions herein can contain, per unit dosage unit, from about 10 toabout 1000 mg of the active ingredient, e.g., from about 25 to about 600mg of the active ingredient, e.g., from about 75 to about 400 mg of theactive ingredient, e.g., about 25, 50, 75, 100, 125, 150, 175, 200, 225,250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, or600 mg or more or any range therein.

In some embodiments of the present invention, carbamate compoundssuitable for use in the practice of this invention will be administeredeither singly or concomitantly with at least one or more other compoundsor therapeutic agents, e.g., with other agents that treat cataplexyand/or other disorders or symptoms associated with cataplexy ornarcolepsy (e.g., excessive daytime sleepiness, hypnagogichallucinations, and sleep paralysis). Examples of therapeutic agents fortreating cataplexy include, without limitation, antidepressants (e.g.,tricyclics (such as clomiprimine, imipramine, and protriptyline) andselective serotonin reuptake inhibitors (such as fluoxetine, paroxetine,sertraline, citalopam)) and sodium oxybate (gamma-hydroxybutyrate[GHB]). Therapeutic agents for treating excessive daytime sleepiness andother symptoms of narcolepsy include, without limitation, amphetamines(such as dexamphetamine, methamphetamine, and methylphenidate),modafinil, armodafinil, atomoxetine, and selegiline. Sodium oxybate isthe only medication known to improve both cataplexy and excessivedaytime sleepiness.

The method includes the step of administering to a patient in need oftreatment an effective amount of one of the carbamate compoundsdisclosed herein in combination with an effective amount of one or moreother compounds or therapeutic agents that have the ability to provideadvantageous combined effects such as the ability to augment the effectsof the compounds of the invention.

Pharmaceutically acceptable salts and esters refers to salts and estersthat are pharmaceutically acceptable and have the desiredpharmacological properties. Such salts include salts that may be formedwhere acidic protons present in the compounds are capable of reactingwith inorganic or organic bases. Suitable inorganic salts include thoseformed with the alkali metals, e.g., sodium and potassium, magnesium,calcium, and aluminum. Suitable organic salts include those formed withorganic bases such as the amine bases, e.g., ethanolamine,diethanolamine, triethanolamine, tromethamine, N methylglucamine, andthe like. Pharmaceutically acceptable salts can also include acidaddition salts formed from the reaction of amine moieties in the parentcompound with inorganic acids (e.g., hydrochloric and hydrobromic acids)and organic acids (e.g., acetic acid, citric acid, maleic acid, and thealkane- and arene-sulfonic acids such as methanesulfonic acid andbenzenesulfonic acid). Pharmaceutically acceptable esters include estersformed from carboxy, sulfonyloxy, and phosphonoxy groups present in thecompounds. When there are two acidic groups present, a pharmaceuticallyacceptable salt or ester may be a mono-acid-mono-salt or ester or adi-salt or ester; and similarly where there are more than two acidicgroups present, some or all of such groups can be salified oresterified.

Compounds named in this invention can be present in unsalified orunesterified form, or in salified and/or esterified form, and the namingof such compounds is intended to include both the original (unsalifiedand unesterified) compound and its pharmaceutically acceptable salts andesters. The present invention includes pharmaceutically acceptable saltand ester forms of Formula I. More than one crystal form of anenantiomer of Formula I can exist and as such are also included in thepresent invention.

A pharmaceutical composition of the invention can optionally contain, inaddition to a carbamate compound, at least one other therapeutic agentuseful in the treatment of cataplexy. For example the carbamatecompounds of Formula I can be combined physically with other compoundsin fixed dose combinations to simplify their administration.

Methods of formulating pharmaceutical compositions have been describedin numerous publications such as Pharmaceutical Dosage Forms: Tablets.Second Edition. Revised and Expanded. Volumes 1-3, edited by Liebermanet al.; Pharmaceutical Dosage Forms: Parenteral Medications. Volumes1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: DisperseSystems. Volumes 1-2, edited by Lieberman et al.; published by MarcelDekker, Inc, the disclosure of each of which are herein incorporated byreference in their entireties and for all purposes.

The pharmaceutical compositions are generally formulated as sterile,substantially isotonic and in full compliance with all GoodManufacturing Practice (GMP) regulations of the U.S. Food and DrugAdministration.

The present invention provides methods of providing treatment forcataplexy in a mammal using carbamate compounds. The amount of thecarbamate compound necessary to provide treatment for cataplexy isdefined as a therapeutically or a pharmaceutically effective dose. Thedosage schedule and amounts effective for this use, i.e., the dosing ordosage regimen will depend on a variety of factors including the stageof the disease, the patient's physical status, age and the like. Incalculating the dosage regimen for a patient, the mode of administrationis also taken into account.

A person of skill in the art will be able without undue experimentation,having regard to that skill and this disclosure, to determine atherapeutically effective amount of a particular substituted carbamatecompound for practice of this invention (see, e.g., Lieberman,Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, 1999, The Art,Science and Technology of Pharmaceutical Compounding; and Pickar, 1999,Dosage Calculations). A therapeutically effective dose is also one inwhich any toxic or detrimental side effects of the active agent isoutweighed in clinical terms by therapeutically beneficial effects. Itis to be further noted that for each particular subject, specific dosageregimens should be evaluated and adjusted over time according to theindividual need and professional judgment of the person administering orsupervising the administration of the compounds.

For treatment purposes, the compositions or compounds disclosed hereincan be administered to the subject in a single bolus delivery, viacontinuous delivery over an extended time period, or in a repeatedadministration protocol (e.g., by an hourly, daily or weekly, repeatedadministration protocol). The pharmaceutical formulations of the presentinvention can be administered, for example, one or more times daily, 3times per week, or weekly. In one embodiment of the present invention,the pharmaceutical formulations of the present invention are orallyadministered once or twice daily.

In this context, a therapeutically effective dosage of the biologicallyactive agent(s) can include repeated doses within a prolonged treatmentregimen that will yield clinically significant results to providetreatment for cataplexy. Determination of effective dosages in thiscontext is typically based on animal model studies followed up by humanclinical trials and is guided by determining effective dosages andadministration protocols that significantly reduce the occurrence orseverity of targeted exposure; symptoms or conditions in the subject.Suitable models in this regard include, for example, murine, rat,porcine, feline, non-human primate, and other accepted animal modelsubjects known in the art. Alternatively, effective dosages can bedetermined using in vitro models (e.g., immunologic and histopathologicassays).

Using such models, only ordinary calculations and adjustments aretypically required to determine an appropriate concentration and dose toadminister a therapeutically effective amount of the biologically activeagent(s) (e.g., amounts that are orally effective intranasallyeffective, transdermally effective, intravenously effective, orintramuscularly effective to elicit a desired response). The effectiveamount, however, may be varied depending upon the particular compoundused, the mode of administration, the strength of the preparation, themode of administration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

In an exemplary embodiment of the present invention, unit dosage formsof the compounds are prepared for standard administration regimens. Inthis way, the composition can be subdivided readily into smaller dosesat the physician's direction. For example, unit dosages can be made upin packeted powders, vials or ampoules and preferably in capsule ortablet form.

Effective administration of the carbamate compounds of this inventioncan be, for example, at an oral or parenteral dose of from about 0.01mg/kg/dose to about 150 mg/kg/dose. For example, administration can befrom about 0.1/mg/kg/dose to about 25 mg/kg/dose, e.g., from about 0.2to about 18 mg/kg/dose, e.g., from about 0.5 to about 10 mg/kg/dose.Therefore, the therapeutically effective amount of the active ingredientcan be, for example, from about 1 mg/day to about 7000 mg/day for asubject having, for example, an average weight of 70 kg, e.g., fromabout 10 to about 2000 mg/day, e.g., from about 50 to about 600 mg/day,e.g., about 10, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300,325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, or 600 mg/day ormore or any range therein. In one embodiment, the compound of Formula Iis administered in the form of a capsule at a dose of about 150 mg toabout 300 mg without any excipients.

The methods of this invention also provide for kits for use in providingtreatment for cataplexy. After a pharmaceutical composition comprisingone or more carbamate compounds of this invention, with the possibleaddition of one or more other compounds of therapeutic benefit, has beenformulated in a suitable carrier, it can be placed in an appropriatecontainer and labeled for providing treatment for cataplexy.Additionally, another pharmaceutical comprising at least one othertherapeutic agent can be placed in the container as well and labeled fortreatment of the indicated disease. Such labeling can include, forexample, instructions concerning the amount, frequency and method ofadministration of each pharmaceutical.

Embodiments according to the present invention are described innon-limiting examples below.

Example 1 Clinical Trial With Narcolepsy Patients

A study of the safety and efficacy of ADX-NOS5 in the treatment ofexcessive daytime sleepiness in subjects with narcolepsy is carried out.The study includes an exploratory analysis of the potential efficacy ofADX-N05 in the subset of narcolepsy subjects in this study who also havecataplexy.

The study is a double-blind, flexible target-dose, placebo-controlled,multi-center, randomized, parallel-group, study. Following thesuccessful completion of a Screening Phase and Baseline Phase, subjectsare randomized to one of two treatment groups and receive ADX-N05 orplacebo over a treatment period of 12 weeks (Treatment Group #1: Weeks1-4: ADX-N05 150 mg/day; Weeks 5-12: ADX-N05 300 mg/day; Treatment Group#2: Weeks 1-12: Placebo) as shown in Table 1. Approximately 90 subjects(45 per treatment group) are enrolled into the study. Each subjectcompletes Screening, Baseline, Treatment, and Follow-up Visits.

TABLE 1 Treatment Schedule Number of capsules Total taken DailyTreatment Week per day Dose Treatment Group # 1: ADX-N05 Weeks 1-4 1 150mg Weeks 5-12 2 300 mg Treatment Group # 2: Placebo Weeks 1-4 1 0 Weeks5-12 2 0

Prior to initiating the 12-week treatment period, subjects complete aScreening Phase of up to 28 days, during which time all screeningassessments are performed and any current narcolepsy treatmentsdiscontinued as well as a Baseline Phase, including an overnight stay atthe investigational site, during which time Baseline efficacy and safetyassessments are obtained. During the Treatment Phase, subjects return tothe investigative site to complete efficacy and safety assessments atthe end of Weeks 1, 2, 4, 6, 8, and 12; the Week 4 and Week 12 Visitsalso include an overnight stay at the investigational site. Subjectstake their final dose of study drug at the Week 12 Visit prior to Week12 Visit assessments. Subjects return at the end of Week 13 for Followup assessments and unless there are any outstanding safety issues thatrequire follow-up, subjects are discharged from the study at that visit.

Exploratory endpoints of the study are: (1) change from Baseline in themedian number of cataplectic attacks per week for the subset of subjectswith cataplexy for ADX-N05 vs. placebo at Week 4 and at last assessment;and (2) primary and secondary efficacy endpoints for the subset ofsubjects with cataplexy. Patients keep a cataplexy diary to track thenumber of episodes. The change from Baseline in median number ofcataplectic attacks per week for the subset of subjects with cataplexyfor ADX-N05 vs. placebo at Week 4 and at last available assessment iscalculated for the subset of subjects with cataplexy in each of thetreatment groups. A Wilcoxon rank-sum test is used to compare the twotreatment groups. The foregoing is illustrative of the presentinvention, and is not to be construed as limiting thereof. The inventionis defined by the following claims, with equivalents of the claims to beincluded therein.

All publications, patent applications, patents and other referencescited herein are incorporated by reference in their entireties for theteachings relevant to the sentence and/or paragraph in which thereference is presented.

1. A method of treating cataplexy in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of Formula (I):

or a pharmaceutically acceptable salt or ester thereof; wherein R is amember selected from the group consisting of hydrogen, lower alkyl of 1to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxycontaining 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, andthioalkoxy containing 1 to 3 carbon atoms; x is an integer of 0 to 3,with the proviso that R may be the same or different when x is 2 or 3;R₁ and R₂ are independently selected from the group consisting ofhydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, arylalkyl,cycloalkyl of 3 to 7 carbon atoms; or R₁ and R₂ can be joined to form a5 to 7-membered heterocycle substituted with a member selected from thegroup consisting of hydrogen, alkyl, and aryl groups, wherein theheterocycle can comprise 1 to 2 nitrogen atoms and 0 to 1 oxygen atom,wherein the nitrogen atoms are not directly connected with each other orwith the oxygen atom; and an additional therapeutic agent.
 2. The methodof claim 1, wherein x=0.
 3. The method of claim 1, wherein R₁ and R₂ arehydrogen and x=0.
 4. The method of claim 1, wherein the compound ofFormula I is an enantiomer of Formula I substantially free of otherenantiomers or an enantiomeric mixture wherein one enantiomer of FormulaI predominates.
 5. (canceled)
 6. The method of claim 4, wherein theenantiomer of Formula I predominates to the extent of about 98% orgreater.
 7. The method of claim 4, wherein the enantiomer of Formula Iis an enantiomer of Formula Ia:

or a pharmaceutically acceptable salt or ester thereof.
 8. The method ofclaim 7, wherein the enantiomer of Formula Ia is the (R) or (D)enantiomer.
 9. The method of claim 7, wherein the enantiomer of FormulaIa is the (S) or (L) enantiomer.
 10. (canceled)
 11. The method of claim7, wherein the enantiomer of Formula Ia predominates to the extent ofabout 98% or greater.
 12. The method of claim 4, wherein the enantiomerof Formula I substantially free of other enantiomers is the compound ofFormula Ib or an enantiomeric mixture wherein the compound of Formula Ibpredominates:

or a pharmaceutically acceptable salt or ester thereof.
 13. (canceled)14. The method of claim 12, wherein the compound of Formula Ibpredominates to the extent of about 98% or greater.
 15. The method ofclaim 1, wherein the cataplexy is associated with narcolepsy.
 16. Themethod of claim 1, wherein the cataplexy is secondary to a conditionthat lowers hypocretin levels in the subject.
 17. The method of claim16, wherein the condition is selected from the group consisting of braintumor, astrocytomas, glioblastoma, glioma, subependynoma,craniopharyngioma, arterio-venous malformations, ischemic events,multiple sclerosis, head injury, brain surgery, paraneoplasticsyndromes, Neimann-Pick type C disease, and encephalitis.
 18. The methodof claim 1, wherein the therapeutically effective amount of the compoundof Formula I is from about 0.01 mg/kg/dose to about 150 mg/kg/dose. 19.The method of claim 1, wherein the therapeutically effective amount ofthe compound of Formula I is from about 1 mg/day to about 7000 mg/day.20. The method of claim 1, wherein the compound of Formula I isadministered orally.
 21. The method of claim 1, wherein the compound ofFormula I is administered in the form of a capsule or tablet. 22.(canceled)
 23. The method of claim 1, wherein the additional therapeuticagent is a therapeutic agent for treating cataplexy.
 24. The method ofclaim 1, wherein the additional therapeutic agent is a therapeutic agentfor treating narcolepsy.
 25. The method of claim 1, wherein the compoundof Formula (I) and the additional therapeutic agent are administered inthe same composition.
 26. The method of claim 1, wherein the compound ofFormula (I) and the additional therapeutic agent are administered inseparate compositions.